Process for production of fluoro derivative

Abstract

It was found that a fluoro derivative can be produced by reacting a hydroxy derivative with sulfuryl fluoride (SO 2 F 2 ) in the presence of an organic base or in the presence of an organic base and “a salt or complex comprising an organic base and hydrogen fluoride”. According to the present production process, it is not necessary to use perfluoroalkanesulfonyl fluoride, which is not preferable in industrial use, and it is possible to advantageously produce optically-active fluoro derivatives, which are important intermediates of medicines, agricultural chemicals and optical materials, specifically 4-fluoroproline derivatives, 2′-deoxy-2′-fluorouridine derivatives, optically-active α-fluorocarboxylate derivatives, and the like, even in a large scale.

1. A process for producing a fluoro derivative, which is represented by the formula [2], 
       
         
           
           
               
               
           
         
       
       by reacting a hydroxy derivative, which is represented by the formula [1], 
       
         
           
           
               
               
           
         
       
       with sulfuryl fluoride (SO 2 F 2 ) in the presence of an organic base,
 wherein in formula [1] and formula [2], each of R, R 1  and R 2  is independently a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group, or an alkoxycarbonyl group. 
 
     
     
       2. A process for producing a fluoro derivative according to  claim 1 , wherein the reaction is conducted by making a salt or complex comprising an organic base and hydrogen fluoride further present in the system. 
     
     
       3. A process for producing a fluoro derivative, which is represented by the formula [2a], 
       
         
           
           
               
               
           
         
       
       by reacting a hydroxy derivative, which is represented by the formula [1a], 
       
         
           
           
               
               
           
         
       
       with sulfuryl fluoride (SO 2 F 2 ) in the presence of an organic base,
 wherein 
 in formula [1a] and formula [2a], each of R, R 1  and R 2  independently represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group, or an alkoxycarbonyl group, 
 the alkyl group is defined as being a C 1 -C 16  straight-chain or branched alkyl group, 
 the substituted alkyl group is defined as being an alkyl group, in which a halogen atom, lower alkoxy group, lower haloalkoxy group, lower alkylamino group, lower alkylthio group, cyano group, aminocarbonyl group (CONH 2 ), unsaturated group, aromatic ring group, nucleic acid base, aromatic-ring oxy group, aliphatic heterocyclic group, protected hydroxyl group, protected amino group, protected thiol group, or protected carboxyl group has been substituted therefor by any number and by any combination on any carbon atom of the alkyl group, 
 any carbon atoms themselves of any two alkyl groups or substituted alkyl groups may form a covalent bond to have an aliphatic ring, and carbon atoms of the aliphatic ring may be partially replaced with a nitrogen atom or oxygen atom to have an aliphatic heterocyclic ring, 
 the aromatic ring group is defined as being an aromatic hydrocarbon group or aromatic heterocyclic group containing oxygen atom, nitrogen atom or sulfur atom, and 
 the alkoxycarbonyl group is defined as being an alkoxycarbonyl group comprising an C 1 -C 12  straight-chain or branched alkoxy group, and any carbon atoms themselves of the alkoxy group and of any alkyl group or substituted alkyl group may form a covalent bond to have a lactone ring. 
 
     
     
       4. A process for producing a fluoro derivative according to  claim 3 , wherein the reaction is conducted by making a salt or complex comprising an organic base and hydrogen fluoride further present in the system. 
     
     
       5. A process for producing an optically-active, fluoro derivative, which is represented by the formula [4], 
       
         
           
           
               
               
           
         
       
       by reacting an optically-active, hydroxy derivative, which is represented by the formula [3], 
       
         
           
           
               
               
           
         
       
       with sulfuryl fluoride (SO 2 F 2 ) in the presence of an organic base,
 wherein 
 in formula [3] and formula [4], each of R and R 1  is independently an alkyl group, a substituted alkyl group, or an alkoxycarbonyl group, 
 * indicates an asymmetric carbon, 
 the alkyl group is defined as being a C 1 -C 16  straight-chain or branched alkyl group, 
 the substituted alkyl group is defined as being an alkyl group, in which a halogen atom, lower alkoxy group, lower haloalkoxy group, lower alkylamino group, lower alkylthio group, cyano group, aminocarbonyl group (CONH 2 ), unsaturated group, aromatic ring group, nucleic acid base, aromatic-ring oxy group, aliphatic heterocyclic group, protected hydroxyl group, protected amino group, protected thiol group, or protected carboxyl group has been substituted therefor by any number and by any combination on any carbon atom of the alkyl group, 
 any carbon atoms themselves of two alkyl groups or substituted alkyl groups may form a covalent bond to have an aliphatic ring, and carbon atoms of the aliphatic ring may be partially replaced with a nitrogen atom or oxygen atom to have an aliphatic heterocyclic ring, 
 the alkoxycarbonyl group is defined as being an alkoxycarbonyl group comprising an C 1 -C 12  straight-chain or branched alkoxy group, and any carbon atoms themselves of the alkoxy group and of any alkyl group or substituted alkyl group may form a covalent bond to have a lactone ring, and 
 stereochemistry of the carbon atom, to which the hydroxyl group is covalently bonded, is inverted through the reaction. 
 
     
     
       6. A process for producing an optically-active, fluoro derivative according to  claim 5 , wherein the reaction is conducted by making a salt or complex comprising an organic base and hydrogen fluoride further present in the system. 
     
     
       7. A process for producing a 4-fluoroproline derivative, which is represented by the formula [6], 
       
         
           
           
               
               
           
         
       
       by reacting a 4-hydroxyproline derivative, which is represented by the formula [5], 
       
         
           
           
               
               
           
         
       
       with sulfuryl fluoride (SO 2 F 2 ) in the presence of an organic base,
 wherein in formula [5] and formula [6], R 3  represents a protecting group of the secondary amino group, R 4  represents a protecting group of the carboxyl group, * indicates an asymmetric carbon, and stereochemistry of the 4-position is inverted through the reaction, and stereochemistry of the 2-position is maintained. 
 
     
     
       8. A process for producing a 4-fluoroproline derivative according to  claim 7 , wherein the reaction is conducted by making a salt or complex comprising an organic base and hydrogen fluoride further present in the system. 
     
     
       9. A process for producing a 2′-deoxy-2′-fluorouridine derivative, which is represented by the formula [8], 
       
         
           
           
               
               
           
         
       
       by reacting a 1-β-D-arabinofuranosyluracil derivative, which is represented by the formula [7], 
       
         
           
           
               
               
           
         
       
       with sulfuryl fluoride (SO 2 F 2 ) in the presence of an organic base,
 wherein in formula [7] and formula [8], each of R 5  and R 6  independently represents a protecting group of the hydroxyl group. 
 
     
     
       10. A process for producing a 2′-deoxy-2′-fluorouridine derivative according to  claim 9 , wherein the reaction is conducted by making a salt or complex comprising an organic base and hydrogen fluoride further present in the system. 
     
     
       11. A process for producing an optically-active, α-fluorocarboxylate derivative, which is represented by the formula [10], 
       
         
           
           
               
               
           
         
       
       by reacting an optically-active, α-hydroxycarboxylate derivative, which is represented by the formula [9], 
       
         
           
           
               
               
           
         
       
       with sulfuryl fluoride (SO 2 F 2 ) in the presence of an organic base,
 wherein in formula [9] and formula [10], R 7  represents a C 1 -C 12  alkyl group or a substituted alkyl group, R 8  represents a C 1 -C 8  alkyl group, any carbon atoms themselves of the alkyl group or of the substituted alkyl group of R 7  and R 8  may form a covalent bond to have a lactone ring, * indicates an asymmetric carbon, and stereochemistry of the α-position is inverted through the reaction. 
 
     
     
       12. A process for producing an optically-active, α-fluorocarboxylate derivative according to  claim 11 , wherein the reaction is conducted by making a salt or complex comprising an organic base and hydrogen fluoride further present in the system. 
     
     
       13. A process for producing a monofluoromethyl derivative, which is represented by the formula [12], 
       
         
           
           
               
               
           
         
       
       by reacting a primary alcohol derivative, which is represented by the formula [11], 
       
         
           
           
               
               
           
         
       
       with sulfuryl fluoride (SO 2 F 2 ) in the presence of an organic base,
 wherein in formula [11] and formula [12], R represents an alkyl group or a substituted alkyl group, 
 the alkyl group is defined as being a C 1 -C 16  straight-chain or branched alkyl group, 
 the substituted alkyl group is defined as being an alkyl group, in which a halogen atom, lower alkoxy group, lower haloalkoxy group, lower alkylamino group, lower alkylthio group, cyano group, aminocarbonyl group (CONH 2 ), unsaturated group, aromatic ring group, nucleic acid base, aromatic-ring oxy group, aliphatic heterocyclic group, protected hydroxyl group, protected amino group, protected thiol group, or protected carboxyl group has been substituted therefor by any number and by any combination on any carbon atom of the alkyl group. 
 
     
     
       14. A process for producing a monofluoromethyl derivative according to  claim 13 , wherein the reaction is conducted by making a salt or complex comprising an organic base and hydrogen fluoride further present in the system.